Abstract
A Science Translational Medicine paper details a clinical trial for a type of T-cell receptor therapy in which two patients died of heart failure. The group published their results to share methods for identifying other peptides to which these engineered cells can bind.
Cancer therapies that use engineered T cells to attack tumors have demonstrated promise in clinical trials, in some cases achieving complete remission in patients. However, some tragic results in recent trials highlight safety concerns.
A paper published in Science Translational Medicine in August details a clinical trial for a type of T-cell receptor (TCR) therapy, in which patients' T cells were engineered to express a TCR that recognizes a peptide from the cancer-testis antigen MAGE A3 and has an enhanced affinity for it. Sadly, two patients who received the engineered T cells died of heart failure a few days later, and the trial was halted.
Nicholas Pumphrey, PhD, head of pipeline research at Adaptimmune, in Oxford, UK, the company that developed the therapy, says that MAGE A3 is not found in the heart, and extensive safety testing beforehand did not identify other antigens in normal tissues that the TCR might target. However, further investigation found that the TCR could also bind to a peptide from the muscle protein Titin, which is expressed in cardiac muscle cells in vivo but not in cultured cells typically used for safety testing.
Pumphrey says the group published the results to share methods for identifying Titin and other peptides to which these cells might bind, in hopes of preventing “off-target” toxicity in other clinical trials. “The tools we used to identify Titin are now being used to safety-test our new TCRs, meaning that future programs will be safer,” he says.
Another clinical trial for a MAGE A3–specific TCR therapy, headed by the National Cancer Institute, led to two patient deaths because the cells recognized an epitope of the antigen in the brain. Michel Sadelain, MD, PhD, director of the Center for Cell Engineering at Memorial Sloan-Kettering Cancer Center in New York, NY, says that “T-cell receptors are going to have to undergo a more complex vetting process to be brought to the clinic.” TCR therapies have been attractive because of their potency, he adds, but “when you can make powerful T cells, the subtlety of discriminating normal cells from tumor cells becomes critical.”
A second type of T-cell therapy uses chimeric antigen receptors (CAR), which are artificial antibody-like receptors that bind to specific targets on the surface of cancer cells. Sadelain says that it's more straightforward to identify potential off-target effects of these surface-binding molecules.
Daniel Powell, PhD, director of the Cellular Therapy Tissue Facility at the University of Pennsylvania School of Medicine in Philadelphia, says that after some CAR therapies failed to show persistent effects, costimulatory molecules were introduced to increase their activity.
“We can now fortify CAR T cells with costimulatory domains that send proliferation and survival signals to T cells,” he says, “which allows them to persist after infusion and achieve remarkable cancer eradication.” With a great deal of optimism in the field, the question now, he adds, is “how widespread can this application be made?”